General regression model: A "model-free" association test for quantitative traits allowing to test for the underlying genetic model.

Most genome-wide association studies used genetic-model-based tests assuming an additive mode of inheritance, leading to underpowered association tests in case of departure from additivity. The general regression model (GRM) association test proposed by Fisher and Wilson in 1980 makes no assumption on the genetic model. Interestingly, it also allows formal testing of the underlying genetic model. We conducted a simulation study of quantitative traits to compare the power of the GRM test to the classical linear regression tests, the maximum of the three statistics (MAX), and the allele-based (allelic) tests. Simulations were performed on two samples sizes, using a large panel of genetic models, varying genetic models, minor allele frequencies, and the percentage of explained variance. In case of departure from additivity, the GRM was more powerful than the additive regression tests (power gain reaching 80%) and had similar power when the true model is additive. GRM was also as or more powerful than the MAX or allelic tests. The true simulated model was mostly retained by the GRM test. Application of GRM to HbA1c illustrates its gain in power. To conclude, GRM increases power to detect association for quantitative traits, allows determining the genetic model and is easily applicable.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Deprivation and health risk indicators in full-time permanent workers.

BACKGROUND: Association between deprivation and health is well established, particularly among unemployed or fixed-term contract or temporary contract subjects. This study aimed to assess if this relationship existed as well in full-time permanent workers. METHODS: Biometrical, biological, behavioural and psychosocial health risk indicators and an individual deprivation score, the Evaluation of Precarity and Inequalities in Health Examination Centres score, were recorded from January 2007 to June 2008, in 34 905 full-time permanent workers aged 18-70 years, all volunteers for a free health examination. Comparisons of the behavioural, metabolic, cardiovascular and health risk indicators between quintiles of the deprivation score with adjustments on age and socioeconomic categories were made by covariance analysis or logistic regression. RESULTS: For both genders, degradation of nutritional behaviours, metabolic and cardiovascular indicators and health appeared gradually with deprivation, even for deprivation score usually considered as an insignificant value. The absence of only one social support or one social network was associated with a degradation of health. Full-time permanent workers with the poorest health risk indicators had more frequent social exclusion signs. These results were independent of socioeconomic categories and age. CONCLUSION: Understanding how deprivation influences health status may lead to more effective interventions to reduce social inequalities in health. The deprivation Evaluation of Precarity and Inequalities in Health Examination Centres score is a relevant tool to detect subjects who could benefit from preventive interventions. Our findings suggest that this deprivation score should be used as a health risk indicator even in full-time permanent workers. Assessing deprivation is useful to design and evaluate specific intervention programmes.

Serum concentrations of insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3), IGF-1/IGFBP-3 ratio, and markers of bone turnover: reference values for French children and adolescents and z-score comparability with other references.

BACKGROUND: A reference model for converting serum growth factor and bone metabolism markers into an SD score (SDS) is required for clinical practice. We aimed to establish reference values of serum insulin-like growth factor-1 (IGF-1) and IGF binding protein 3 (IGFBP-3) concentrations and bone metabolism markers in French children, to generate a model for converting values into SDS for age, sex, and pubertal stage. METHODS: We carried out a cross-sectional study of 1119 healthy white children ages 6-20 years. We assessed concentrations of serum IGF-1, IGFBP-3, carboxyterminal telopeptide α1 chain of type I collagen (CrossLaps), and bone alkaline phosphatase concentrations and height, weight, and pubertal stage, and used semiparametric regression to develop a model. RESULTS: A single regression model to calculate the SDSs with an online calculator was provided. A positive relationship was found between SDS for serum IGF-1 and IGFBP-3, IGF/IGFBP-3 mol/L ratio, and anthropometric parameters (P < 0.0001), with slightly greater effects observed for height than for body mass index (BMI). There was a negative relationship between serum CrossLaps concentration and BMI, and a positive relationship between serum CrossLaps concentration and height. A comparison of serum IGF-1 reference databases for children showed marked variation as a function of age and pubertal group; smooth changes with age and puberty were observed only in our model. CONCLUSIONS: This new model for the assessment of SDS reference values specific for age, sex, and pubertal stage may help to increase the diagnostic power of these parameters for the assessment of growth and bone metabolism disorders. This study also provides information about the physiological role of height and BMI for the interpretation of these parameters.

[Age and sex variations of HbA(1C) in a French population without known diabetes aged 6 to 79 years]. / Évolution de l'HbA(1C) en fonction de l'âge et du sexe dans une population française de sujets sans diabète connu âgés de 6 à 79 ans.

HbA(1C) is being used for screening and diagnosing diabetes. We determined mean values of HbA(1C) according to age and sex in a large population without known diabetes, in a wide age range 6-79  years. 5,138 men and women without known diabetes aged 6-79  years participated in a routine health examination provided by their medical insurance. HbA(1C) was assessed on an HPLC analyzer aligned with a DCCT method. HbA(1C) was approximately normally distributed in both men and women. Mean (SD) HbA(1C) were, for men vs women, in percentages 5.3 (0.4) vs 5.2 (0.3), in mmol/mol 34 (5) vs 34 (4) and in estimated blood glucose in mmol/L 5.83 (0.67) vs 5.75 (0.53). HbA(1C) increased with age by 0.08% every 10  years and this was attenuated to a 0.04% increase after adjustment on fasting plasma glucose. Between 15 and 49  years, women had lower values than men (p < 0.0001), but no sex differences were observed before and after this age range. In our population, 0.6% had HbA(1C) greater or equal to 6.5% and 88% (96% of men and 73% of women) of them had fasting plasma glucose greater or equal to 6,1 mmol/L. Threshold of 6.0% selected 2.8% of our population.

R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population.

Stone et al. previously reported an association between the TBC1D1 gene variant R125W (rs35859249) and severe obesity in women from US pedigrees. We attempted to replicate this result in 9714 French Caucasian individuals, combining family-based and general population studies. We confirmed an association with familial obesity (defined as body mass index (BMI) > or = 97th percentile) in women from 1109 obesity-selected pedigrees (Z-score = 2.70, P = 0.008). Analysis of 16 microsatellite markers on chromosome 4 restricted to the 42 pedigrees carrying the TBC1D1 R125W variant allele also revealed a suggestive evidence of linkage with obesity (maximum likelihood binomial LOD of 2.73, P = 0.0002) on chromosome 4p14, where resides TBC1D1. In contrast, R125W variant was neither associated with BMI nor with obesity in a large population-based cohort. These results confirm a putative role of TBC1D1 R125W variant in familial obesity predisposition.

Performance of immunochemical faecal occult blood test in colorectal cancer screening in average-risk population according to positivity threshold and number of samples.

Immunochemical faecal occult blood tests (I-FOBT) detect more effectively advanced neoplasia than guaiac tests (G-FOBT). The study aim was to compare the performance of an I-FOBT whilst varying the positivity threshold and considering four analysis modalities: one sample was performed (MG(1)), two samples were performed and at least one sample was positive (MG(2+)), both samples were positive (MG(2++)) or the mean of the two samples' log-transformed haemoglobin contents exceeded the cutoff (MG(2m)). Screening for colorectal cancer using both G-FOBT and two samples' I-FOBT was performed by an average-risk population sample of 20,322 subjects. Among the 1,615 subjects with at least one positive test, 1,277 had a satisfactory colonoscopy result; 43 invasive cancers and 270 high-risk adenomas were detected. The I-FOBT was reinterpreted under each analysis modality (a random selection of one sample led to MG(1)). For all modalities, increasing the positivity threshold decreased sensitivity and increased specificity. The relative ROC curves (in reference to G-FOBT) demonstrated similar performance for MG(1) and MG(2+), and improved performance for MG(2m). MG(2++) sensitivity was limited within the range of positivity thresholds evaluated. For any specificity, MG(2m) provided the highest sensitivity. For any sensitivity, MG(2m) provided the highest specificity. For any positivity rate, MG(2m) provided both the highest sensitivity and specificity. This study suggests the replacement of MG(2+) by MG(1) or, for even better performance, by MG(2m) provided that two samples are performed with similar participation (which should be explored). The targeted positivity rate could then be achieved by choosing the positivity threshold.

Evaluating the association of common APOA2 variants with type 2 diabetes.

BACKGROUND: APOA2 is a positional and biological candidate gene for type 2 diabetes at the chromosome 1q21-q24 susceptibility locus. The aim of this study was to examine if HapMap phase II tag SNPs in APOA2 are associated with type 2 diabetes and quantitative traits in French Caucasian subjects. METHODS: We genotyped the three HapMap phase II tagging SNPs (rs6413453, rs5085 and rs5082) required to capture the common variation spanning the APOA2 locus in our type 2 diabetes case-control cohort comprising 3,093 French Caucasian subjects. The association between these variants and quantitative traits was also examined in the normoglycaemic adults of the control cohort. In addition, meta-analysis of publicly available whole genome association data was performed. RESULTS: None of the APOA2 tag SNPs were associated with type 2 diabetes in the French Caucasian case-control cohort (rs6413453, P = 0.619; rs5085, P = 0.245; rs5082, P = 0.591). However, rs5082 was marginally associated with total cholesterol levels (P = 0.026) and waist-to-hip ratio (P = 0.029). The meta-analysis of data from 12,387 subjects confirmed our finding that common variation at the APOA2 locus is not associated with type 2 diabetes. CONCLUSION: The available data does not support a role for common variants in APOA2 on type 2 diabetes susceptibility or related quantitative traits in Northern Europeans.

Trends in the prevalence of obesity in employed adults in central-western France: a population-based study, 1995-2005.

OBJECTIVE: The overall trend of obesity prevalence has increased during the last decades, even in France which has one of the lowest prevalence in Europe. The aim of this study was to assess, according to socioeconomic status (SES), whether a shift in the obesity prevalence trends could be observed since the French National Nutrition and Public Health Program was implemented in 2001. METHODS: Standardised cross-sectional repeated population-based data from the French Social Security Health Examination Centers in the central-western region of France (n=339,882). We examined regression slopes (95% CI) of overall and abdominal obesity from 1995 to 2005 according to SES. We also compared slopes within each SES between 1995-2001 and 2001-2005. RESULTS: After standardisation to the French age distribution, 6.9% of men and 6.4% of women were obese in 1995 and 8.9% and 8.6% in 2005, respectively. Abdominal adiposity concerned 5.6% of men and 8.5% of women in 1995 and 9.5% and 14.3% in 2005. Obesity prevalence regression slopes between 1995 and 2005 increased in all SES categories, except management professionals in both genders and office/service personnel male who were stable. Significant regression slopes before 2001 became non-significant afterward in office/service personnel males for obesity prevalence; and for abdominal obesity in manual workers women and office/service personnel (p=0.05, in men). CONCLUSIONS: Our data confirm the overall epidemic rise in the obesity prevalence trends during the last decade, except in management professionals and office/service personnel men. Obesity prevalence trends in office/service personnel and manual workers women for abdominal obesity were also observed to stabilise since 2001. We could hypothesize that the National Nutrition and Public Health Program may partly be involved in this decreasing trend among office/service personnel mainly. Policymakers should take into account these data to assess the effectiveness of obesity prevention public-health strategies in the future.

Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study.

Recently, Genome Wide Association (GWA) studies identified novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D) in several case-control studies of European descent. However, the impact of these markers on glucose homeostasis in a population-based study remains to be clarified. The French prospective D.E.S.I.R. study (N = 4,707) was genotyped for 22 polymorphisms within 14 loci showing nominal to strong association with T2D in recently published GWA analyses (CDKAL1, IGFBP2, CDKN2A/2B, EXT2, HHEX, LOC646279, SLC30A8, MMP26, KCTD12, LDLR, CAMTA1, LOC38776, NGN3 and CXCR4). We assessed their effects on quantitative traits related to glucose homeostasis in 4,283 normoglycemic middle-aged participants at baseline and their contribution to T2D incidence during 9 years of follow-up. Individuals carrying T2D risk alleles of CDKAL1 or SLC30A8 had lower fasting plasma insulin level (rs7756992 P = 0.003) or lower basal insulin secretion (rs13266634 P = 0.0005), respectively, than non-carriers. Furthermore, NGN3 and MMP26 risk alleles associated with higher fasting plasma glucose levels (rs10823406 P = 0.01 and rs2499953 P = 0.04, respectively). However, for these SNPs, only modest associations were found with a higher incidence of T2D: hazard ratios of 2.03 [1.00-4.11] for MMP26 (rs2499953 P = 0.05) and 1.33 [1.02-1.73] for NGN3 (rs10823406 P = 0.03). We confirmed deleterious effects of SLC30A8, CDKAL1, NGN3 and MMP26 risk alleles on glucose homeostasis in the D.E.S.I.R. prospective cohort. However, in contrast to TCF7L2, the contribution of novel loci to T2D incidence seems only modest in the general middle-aged French population and should be replicated in larger cohorts.

[Drug treatment of cardiovascular risk factors over six years of following the French DESIR cohort]. / Traitement des facteurs de risque cardiovasculaire dans la cohorte DESIR.

OBJECTIVE: To describe the treatment of cardiovascular risk factors within the context of a cohort study of adults, according to the risk estimated by the Framingham equation. METHOD: This prospective study, DESIR, followed 1526 men and 1652 women for six years. At the time of the study's initiation, all participants were aged 35 to 65, and none were being treated for hypertension or dyslipemia. Treatments for hypertension and dyslipemia initiated during the study were analyzed according to categories of cardiovascular risk based on the Framingham scale. RESULTS: At baseline, 24% of men and 5% of women had an estimated 10 years cardiovascular risk (for CHD) higher or equal to 10%. Three years later, only 19% of these men and 36% of these women had been treated, while 6% of men and 9% of women at risk < 10% had also been treated well. At six years, one third of men at high risk at baseline and/or at three years were treated, against half of the women. CONCLUSION: Despite a significant effort to communicate the importance of addressing and treating the individual risk factors, the currently prescribed treatments remain inadequate, especially given the necessity to treat them based on the assessment of the overall cardiovascular risk.

Urinary albumin excretion is a risk factor for diabetes mellitus in men, independently of initial metabolic profile and development of insulin resistance. The DESIR Study.

BACKGROUND: Elevated urinary albumin excretion (UAE) is more frequent in patients with the metabolic syndrome or insulin resistance. Whether UAE predicts the development of diabetes mellitus, independently of the presence or the development of the metabolic syndrome, is unclear, in particular, in women. OBJECTIVE: We prospectively assessed the association between baseline UAE and subsequent diabetes mellitus in participants selected from the general population. PARTICIPANTS AND METHODS: Four thousand and seventy-four nondiabetic patients (aged 30-64 years) included in the Data from an Epidemiological Study on the Insulin Resistance syndrome Study had a baseline UAE. Among them, 3851 patients had complete data regarding diabetes mellitus. RESULTS: Diabetes mellitus occurred in 171 out of 3851 patients during the 9-year follow-up (132/2056 men and 39/1795 women). UAE was associated with diabetes mellitus in a dose-dependent manner in men [as compared to men with UAE<9 mg/l, hazard ratios were 1.81 (P=0.0160), 1.83 (P=0.0134), 2.31 (P=0.0008) and 4.43 (P=0.0005) for men with UAE: 9-12 mg/l, 12-19 mg/l, 20-200 mg/l and >200 mg/l, respectively] but not in women; the association was more marked after exclusion of men with baseline impaired fasting glucose [hazard ratios were 3.28 (P=0.0007), 3.08 (P=0.0012), 3.27 (P=0.0022), 9.23 (P<0.0001), respectively]. The association remained significant after adjustments on BMI, sporting activity, diet, smoking, waist circumference, insulin and homeostasis model assessment of insulin resistance, lipids, C-reactive protein and family of history of diabetes mellitus. Adjustment on the first 3-year change in weight, glucose, insulin and homeostasis model assessment of insulin resistance did not modify the results. CONCLUSION: Elevated UAE predicts the 9-year risk of diabetes mellitus in men, independent of baseline or early development of metabolic abnormalities or insulin resistance.

The Data from an Epidemiologic Study on the Insulin Resistance Syndrome Study: the change and the rate of change of the age-blood pressure relationship.

OBJECTIVE: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) increase significantly until around 55 years, when SBP increases, DBP decreases. Whether the rates of change of SBP and DBP with age exhibit a similar dissociation has never been investigated. DESIGN AND PARTICIPANTS: The Data from an Epidemiologic Study on the Insulin Resistance Syndrome Study (D.E.S.I.R.), a 9-year longitudinal study included 2278 men and 2314 women, 30-65 years and SBP, DBP, and other cardiometabolic risk factors were determined every 3 years. RESULTS: Both SBP and DBP increased with age, more rapidly in women than in men. SBP and DBP were higher in the presence of risk factors (except smoking) but the increases with age were similar. For the rates of change, whereas DeltaSBP increased linearly with age, DeltaDBP declined as early as 45 years. This finding was not influenced by sex, menopause or other risk factors but was significantly attenuated in the presence of hypertension at baseline, whether treated or not, and mainly in men. CONCLUSION: DBP increases with age between 30 and 60 years, DeltaDBP tends to be markedly reduced as early as 45 years, in contrast with DeltaSBP. Consequences for the understanding of vascular aging and antihypertensive therapy remain to be explored.

Evaluating the association of common PBX1 variants with type 2 diabetes.

BACKGROUND: PBX1 is a biological candidate gene for type 2 diabetes at the 1q21-q24 susceptibility locus. The aim of this study was to evaluate the association of common PBX1 variants with type 2 diabetes in French Caucasian subjects. METHODS: Employing a case-control design, we genotyped 39 SNPs spanning the PBX1 locus in 3,093 subjects to test for association with type 2 diabetes. RESULTS: Several PBX1 SNPs, including the G21S coding SNP rs2275558, were nominally associated with type 2 diabetes but the strongest result was obtained with the intron 2 SNP rs2792248 (P = 0.004, OR 1.20 [95% CI 1.06-1.37]). The SNPSpD multiple testing correction method gave a significance threshold of P = 0.002 for the 39 SNPs genotyped, indicating that the rs2792248 association did not survive multiple testing adjustment. SNP rs2792248 did not show evidence of association with the French 1q linkage signal (P = 0.31; weighted NPL score 2.16). None of the PBX1 SNPs nominally associated with type 2 diabetes were associated with a range of quantitative metabolic traits in the normoglycemic control subjects CONCLUSION: The available data does not support a major influence of common PBX1 variants on type 2 diabetes susceptibility or quantitative metabolic traits. In order to make progress in identifying the elusive susceptibility variants in the 1q region it will be necessary to carry out further large association studies, meta-analyses of existing data from individual studies, and deep resequencing of the 1q region.

Aging Male Questionnaire in normal and complaining men.

INTRODUCTION: Detection of androgen deficiency is at least, based on specific questionnaires, defined by sexual, psychological, and somatic variables. Their relationships with sexual hormone levels are poorly understood. AIM: To assess the Aging Male Symptoms (AMS) score and sex hormone levels in normal and complaining men in order to define the relationship between the key parameters related to androgen deficiency. METHODS: Nine hundred and three men were interviewed via phone by a trained interviewer who completed the questionnaire; 539 men consulting for a checkup in a health center and 471 complaining men, who completed the AMS scale in clinical setting, were selected, after excluding subjects with major and/or chronic diseases, endocrine disorders, psychological dysfunctions, and metabolic syndrome. MAIN OUTCOME MEASURES: Total AMS score and psychological, somatic and sexual subscores, as a function of age. RESULTS: The AMS questionnaires the were completed in a clinical setting or via calling-up line were comparable. In both cases, total AMS scores and subscores were significantly dependent of age and were correlated to income. In normal men, the only two parameters that significantly changed with age were the AMS sexual subscore and bioavailable testosterone (BT). Complaining men aged more than 50 years old had a significantly higher total AMS scores, subscores, and BT level than normal men up to 60 years old, and these differences weakened with increasing age. In normal and complaining men, whatever the AMS sexual subscore, any variation in testosterone (T) and BT levels was observed. CONCLUSIONS: The AMS scale could be defined as a screening test for androgen deficiency symptoms in men between 50 and 65 years of age. The sexual AMS subscore and BT level are the key variables to identify those symptoms; the severity of sexual symptoms can not be explained by a BT level decrease.

The PPARG Pro12Ala polymorphism is associated with a decreased risk of developing hyperglycemia over 6 years and combines with the effect of the APM1 G-11391A single nucleotide polymorphism: the Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study.

Although cross-sectional studies have associated the Pro12Ala polymorphism of PPARG with type 2 diabetes, prospective studies offer more opportunities to investigate genetic variants. Associations between PPARG polymorphisms with insulin resistance parameters and with the 6-year incidence of impaired fasting glucose or type 2 diabetes were tested in 3,914 French Caucasians from the DESIR (Data From an Epidemiological Study on the Insulin Resistance Syndrome) cohort. In subjects normoglycemic at baseline (n = 3,498), the 6-year risk of hyperglycemia was lower in PPARG Ala carriers (odds ratio [OR] vs. ProPro = 0.66 [95% CI 0.44-0.99], P = 0.046 adjusted for sex, age, and BMI). Similar results were found with the PPARG C1431T single nucleotide polymorphism (SNP; adjusted OR = 0.65 [0.44-0.96], P = 0.036). Both alleles are in strong linkage disequilibrium (D' = 0.669, P < 0.001). The baseline mean fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in Ala carriers compared with ProPro homozygotes (P = 0.001 for both), with smaller increases in mean insulin and HOMA-IR during follow-up (P = 0.007 and 0.018, respectively). No association with insulin levels or HOMA-IR was found with C1431T. In this cohort, the APM1 G-11391A SNP is associated with the development of hyperglycemia. The combined effects of PPARG Pro12Ala and APM1 G-11391A SNPs showed no interaction on the risk of 6-year hyperglycemia. The PPARG Ala allele showed a relatively high protective effect in developing hyperglycemia and hyperinsulinemia during a 6-year period. Cumulative rather than synergistic effects of PPARG Pro12Ala and APM1 SNPs on diabetes risk are suggested.

Secretory granule neuroendocrine protein 1 (SGNE1) genetic variation and glucose intolerance in severe childhood and adult obesity.

BACKGROUND: 7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, SGNE1 is located. The aim of this study is to analyze associations of SGNE1 genetic variation with obesity and metabolism related quantitative traits. METHODS: We screened SGNE1 for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort. RESULTS: We did not find any association between SGNE1 SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55-1.01]; p = 0.06) in the prospective cohort. CONCLUSION: SGNE1 genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.

Ferritin and transferrin are both predictive of the onset of hyperglycemia in men and women over 3 years: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study.

OBJECTIVE: The aim of the present work was to determine, in a cohort of men and women, whether ferritin and transferrin were associated with glucose metabolism and whether they were predictive of the onset of hyperglycemia (impaired fasting glycemia or type 2 diabetes) after 3 years of follow-up. RESEARCH DESIGN AND METHODS: Among 4,501 subjects from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, 1,277 subjects (644 men and 633 women) were randomly selected for the analysis of iron biomarkers at baseline and at 3 years. In addition, to determine whether these parameters were relevant to pathological changes, all 231 subjects normoglycemic at baseline and hyperglycemic 3 years later were analyzed for iron biomarkers. RESULTS: At baseline, plasma ferritin concentrations were positively correlated with fasting insulin and fasting glucose in the 1,277 subjects. Although transferrin and ferritin were negatively correlated, transferrin was also positively correlated with fasting insulinemia. Baseline ferritin concentration was an independent predictor of an increase in insulin concentration over a 3-year period (P = 0.002). Further, baseline ferritin and transferrin were independently associated with the onset of hyperglycemia over a 3-year period in the whole population (P < 0.001 for both) and in each sex. CONCLUSIONS: Although negatively correlated, both transferrin and ferritin were positively associated with the onset of abnormalities in glucose metabolism in a prospective study. These results further support the hypothesis of a causative role of iron metabolism in the onset of insulin resistance and type 2 diabetes.

Use of HbA1c in predicting progression to diabetes in French men and women: data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR).

OBJECTIVE: Early identification of subjects at high risk for diabetes is essential, and random HbA(1c) (A1C) may be more practical than fasting plasma glucose (FPG). The predictive value of A1C, in comparison to FPG, is evaluated for 6-year incident diabetes. RESEARCH DESIGN AND METHODS: From the French cohort study Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR), 1,383 men and 1,437 women, aged 30-65 years, were volunteers for a routine health check-up. Incident diabetes was defined by FPG >or=7.0 mmol/l or treatment by antidiabetic drugs. Multivariate logistic regression models were used to predict diabetes at 6 years. Receiver operating characteristic curves compared the predictive values of A1C and FPG. RESULTS: At 6 years, 30 women (2.1%) and 60 men (4.3%) had developed diabetes. Diabetes risk increased exponentially with A1C in both sexes (P < 0.001). After stratifying on FPG, A1C predicted diabetes only in subjects with impaired fasting glucose (IFG) (FPG >or=6.10 mmol/l): the odds ratio (95% CI) for a 1% increase in A1C was 7.20 (3.00-17.00). In these subjects, an A1C of 5.9% gave an optimal sensitivity of 64% and specificity of 77% to predict diabetes. CONCLUSIONS: A1C predicted diabetes, even though the diagnosis of diabetes was based on FPG, but it was less sensitive and specific than FPG. It could be used as a test if fasting blood sampling was not available or in association with FPG. In subjects with IFG, A1C is better than glucose to evaluate diabetes risk, and it could be used to select subjects for intensive early intervention.

Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studies.

OBJECTIVE: We hypothesized that liver markers and the fatty liver index (FLI) are predictive of incident hypertension and that hepatic insulin resistance plays a role. METHODS: The association between liver markers and incident hypertension was analysed in two longitudinal studies of normotensive individuals, 2565 from the 9-year data from an epidemiological study on the insulin resistance cohort and the 321 from the 3-year 'Relationship between Insulin Sensitivity and Cardiovascular disease' cohort who had a measure of endogenous glucose production. The FLI is calculated from BMI, waist circumference, triglycerides and gamma-glutamyltransferase (GGT) and the hepatic insulin resistance index from endogenous glucose production and fasting insulin. RESULTS: The incidence of hypertension increased across the quartiles groups of both baseline GGT and alanine aminotransferase. After adjustment for sex, age, waist circumference, fasting glucose, smoking and alcohol intake, only GGT was significantly related with incident hypertension [standardized odds ratio: 1.21; 95% confidence interval (1.10-1.34); P = 0.0001]. The change in GGT levels over the follow-up was also related with an increased risk of hypertension, independently of changes in body weight. FLI analysed as a continuous value, or FLI at least 60 at baseline were predictive of incident hypertension in the multivariable model. In the RISC cohort, the hepatic insulin resistance index was positively related with the risk of 3-year incident hypertension [standardized odds ratio: 1.54 (1.07-2.22); P = 0.02]. CONCLUSION: Baseline GGT and FLI, as well as an increase in GGT over time, were associated with the risk of incident hypertension. Enhanced hepatic insulin resistance predicted the onset of hypertension and may be a link between liver markers and hypertension.